Lercanidipine decreases vascular matrix metalloproteinase-2 activity and protects against vascular dysfunction in diabetic rats.
Abnormal matrix metalloproteinases (MMPs) activity causes cardiovascular diseases. Because hyperglycemia increase MMPs activities through increased oxidative stress, we hypothesized that antioxidant effects produced by lercanidipine could attenuate the increases in MMP-2 expression/activity in diabetic rats. Control and diabetic (alloxan-induced diabetes) rats received lercanidipine 2.5 mg/kg/day (or tap water) starting three weeks after alloxan (or vehicle) injections. Blood pressure was monitored weekly. After six weeks of treatment, vascular reactivity and structural changes were assessed in aortic rings. MMP-2 levels were determined by gelatin zymography, and MMP-2/tissue inhibitor of metalloproteinases (TIMP)-2 mRNA levels were determined by quantitative real time RT-PCR. Plasma thiobarbituric acid reactive substances concentrations were determined by fluorimetry. Lercanidipine produced antihypertensive effects (201+/-5 vs. 163+/-7 mm Hg in diabetic rats untreated and treated with lercanidipine, respectively; P<0.01) and reversed the impairment in endothelium-dependent vasorelaxation in diabetic rats. Increased MMP-2 and Pro-MMP-2 levels were found in the aortas of diabetic rats (both P<0.001). Lercandipine attenuated the increases in oxidative stress and in MMP-2 (both P<0.05). While diabetes induced no major structural changes, it caused a 16-fold increase in the ratio of MMP-2/TIMP-2 mRNA expression, which was completely reversed by lercanidipine (both P<0.001). These results show that antioxidant and beneficial vascular effects produced by lercanidipine in diabetic rats are associated with reversion of the imbalance in vascular MMP-2/TIMP-2 expression.
Martinez
Marcio L L
ML
Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, Brazil.
Rizzi
Elen
E
Castro
Michele M
MM
Fernandes
Karla
K
Bendhack
Lusiane M
LM
Gerlach
Raquel F
RF
Tanus-Santos
Jose E
JE
D000496:Alloxan; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology; D004095:Dihydropyridines / Q000494:pharmacology*; D004792:Enzyme Precursors / Q000187:drug effects / Q000378:metabolism; D005470:Fluorometry; D018093:Gelatinases / Q000187:drug effects / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000187:drug effects / Q000378:metabolism
D000959:Antihypertensive Agents; D000975:Antioxidants; D004095:Dihydropyridines; D004792:Enzyme Precursors; D012333:RNA, Messenger; D017392:Thiobarbituric Acid Reactive Substances; D019716:Tissue Inhibitor of Metalloproteinase-2; D000496:Alloxan; D018093:Gelatinases; C069860:progelatinase; D020778:Matrix Metalloproteinase 2; C060343:lercanidipine